Bet Hedging in Yeast by Heterogeneous, Age-Correlated Expression of a Stress Protectant
Open accessAbstract
Genetically identical cells grown in the same culture display striking cell-to-cell heterogeneity in gene expression and other traits. A crucial challenge is to understand how much of this heterogeneity reflects the noise tolerance of a robust system and how much serves a biological function. In bacteria, stochastic gene expression results in cell-to-cell heterogeneity that might serve as a bet-hedging mechanism, allowing a few cells to survive through an antimicrobial treatment while others perish. Despite its clinical importance, the molecular mechanisms underlying bet hedging remain unclear. Here, we investigate the mechanisms of bet hedging in Saccharomyces cerevisiae using a new high-throughput microscopy assay that monitors variable protein expression, morphology, growth rate, and survival outcomes of tens of thousands of yeast microcolonies simultaneously. We find that clonal populations display broad distributions of growth rates and that slow growth predicts resistance to heat killing in a probabalistic manner. We identify several gene products that are likely to play a role in bet hedging and confirm that Tsl1, a trehalose-synthesis regulator, is an important component of this resistance. Tsl1 abundance correlates with growth rate and replicative age and predicts survival. Our results suggest that yeast bet hedging results from multiple epigenetic growth states determined by a combination of stochastic and deterministic factors.
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From the perspective of population evolution, heteroresistance can be seen as a strategy that helps the fungal population survive diverse environments.
“From the perspective of population evolution, it can be seen as a strategy that helps the fungal population survive diverse environments [100].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [100]
The Discussion describes heterogeneous yeast states that confer different fitness across environments, supporting the population-level bet-hedging interpretation. But the paper studies variation in heat-stress survival, not heteroresistance, and Box 1 says whether this bet hedging is adaptive remains to be tested. It therefore does not establish that heteroresistance helps fungal populations survive diverse environments. (LLM, conf=0.85)
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Labhsetwar, P., Melo, M. C. R., Cole, J. A., & Luthey-Schulten, Z. (2017) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1005728 · Cited by 21 · see citing works
El Meouche, I., Jain, P., Jolly, M. K., & Capp, J.-P. (2024) · Translational Oncology · doi:10.1016/j.tranon.2024.102069 · Cited by 22 · see citing works
Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance
Su, Y., Li, Y., Yi, Q., Xu, Y., Sun, T., & Li, Y. (2025) · Journal of Fungi · doi:10.3390/jof11020143 · Cited by 18 · see citing works
“From the perspective of population evolution, it can be seen as a strategy that helps the fungal population survive diverse environments [100].”
A CO <sub>2</sub> sensing module modulates β-1,3-glucan exposure in <i>Candida albicans</i>
Avelar, G. M., Pradhan, A., Ma, Q., Hickey, E., Leaves, I., Liddle, C., Rodriguez Rondon, A. V., Kaune, A.-K., Shaw, S., Maufrais, C., et al. (2024) · mBio · doi:10.1128/mbio.01898-23 · Cited by 15 · see citing works
- Authors
- Levy, S. F., Ziv, N., & Siegal, M. L.
- Affiliations
- New York University (US)
- Corresponding author
- Levy, Sasha F.
- Siegal, Mark L.
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-05-08
- Volume
- 10
- Issue
- 5
- Pages
- e1001325
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC3348152
- OpenAlex
- W1967330678
- Cited by
- 371
- References
- 93
- Citations by year
- 2026: 21 · 2025: 21 · 2024: 27 · 2023: 19 · 2022: 23 · 2021: 29 · 2020: 25 · 2019: 14 · 2018: 34 · 2017: 32 · 2016: 25 · 2015: 36 · 2014: 32 · 2013: 27 · 2012: 6
- FWCI
- 12.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Science Foundation (0642999)
- National Institutes of Health
- National Institute of General Medical Sciences (F32GM079909, F32GM79909)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- bet-hedging, cellular heterogeneity, stochastic gene expression, Saccharomyces cerevisiae, trehalose biosynthesis, growth rate variability, heat resistance, stress tolerance, microcolonies
- MeSH terms
- Flow Cytometry, Genes, Fungal, Hot Temperature, Microscopy, Mutation, Saccharomyces cerevisiae, Stochastic Processes, Time Factors, Colony Count, Microbial, Models, Statistical, Gene Expression Regulation, Fungal, Heat-Shock Response, Saccharomyces cerevisiae Proteins, Epigenesis, Genetic, Green Fluorescent Proteins, Genetic Fitness, Time-Lapse Imaging
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